The primary aim of this project is to understand the genetic and functional relationship between immune responses to major histocompatibility complex (MHC) antigens and to conventional antigens. To this end, the proposed experiments use powerful analytical methods developed very largely during the first two years of the current grant period. Rat alloreactive T cell populations developed by repeated in vitro stimulation with MHC antigens will be used for a serological, chemical and genetic analysis of the T cell receptor for these antigens. The antigens themselves will be analyzed in terms of the topography of their antigenic determinants and of their expression in the membranes of the cells that carry them, using monoclonal anti MHC alloantibodies obtianed from plasma cell hybrids. The molecular location of the determinants against which anti-MHC T cell specificities are directed will be identified using monoclonal anti-MHC alloantibodies of defined specificity as inhibitors of T cell function. The cellular immunology of potent MHC-linked immune response genes governing both alloantibody production and rejection of skin grafts in MHC incompatible combinations will be investigated in depth. Genetic and ontogenetic influences on Ir gene sepcificity will be sought. The genetic control of fine specificity of cytotoxic T lymphocytes will be analyzed using inhibition of cytotoxicity by a panel of monoclonal anti-MHC alloantibodies. The general application of the phenomenon of MHC restriction will be extended to T cell reactions to MHC antigens themselves, based on the T-B collaboration and the existence of MHC-linked Ir genes for responses to these antigens. Finally a reconciliation will be sought between the existence of the large population of alloreactive T cells and the confinement of MHC restricted T cell responses to non-MHC antigens to a smaller non-overlapping population of cells seemingly restricted to self MHC specificities.